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1. Optical genome mapping identifies a homozygous deletion in the non-coding region of the SCN9A gene in individuals from the same family with congenital insensitivity to pain

Author

Aïcha Boughalem, Viorica Ciorna-Monferrato, Natacha Sloboda, Amélie Guegan, François Page, Sophie Zimmer, Marion Benazra, Pascale Kleinfinger, Laurence Lohmann, Mylène Valduga, Aline Receveur, Fernando Martin, and Detlef Trost

Subjects
optical genome mapping, SCN9A gene, insensitivity to pain, non-coding structural variant, structural variant detection, Genetics, QH426-470
Abstract

We report an index patient with complete insensitivity to pain and a history of painless fractures, joint hypermobility, and behavioral problems. The index patient descends from a family with notable cases among his maternal relatives, including his aunt and his mother’s first cousin, both of whom suffer from congenital insensitivity to pain. The patient had normal results for prior genetic testing: fragile-X syndrome testing, chromosomal microarray analysis, and exome sequencing. Optical genome mapping detected a homozygous deletion affecting the noncoding 5′ untranslated region (UTR) and the first non-coding exon of the SCN9A gene in all affected family members, compatible with recessive disease transmission. Pathogenic homozygous loss-of-function variants in the SCN9A gene are associated with impaired pain sensation in humans. Optical genome mapping can thus detect pathogenic structural variants in patients without molecular etiology by standard diagnostic procedures and is a more accessible diagnostic tool than short-read or long-read whole-genome sequencing.

Published
2024
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2. Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis—A Systematic Review

Author

Agustí Alentorn, Giulia Berzero, Harry Alexopoulos, John Tzartos, Germán Reyes Botero, Andrea Morales Martínez, Sergio Muñiz-Castrillo, Alberto Vogrig, Bastien Joubert, Francisco A. García Jiménez, Dagoberto Cabrera, José Vladimir Tobon, Carolina Delgado, Patricio Sandoval, Mónica Troncoso, Lorna Galleguillos, Marine Giry, Marion Benazra, Isaias Hernández Verdin, Maëlle Dade, Géraldine Picard, Véronique Rogemond, Nicolas Weiss, Marinos C. Dalakas, Pierre-Yves Boëlle, Jean-Yves Delattre, Jérôme Honnorat, and Dimitri Psimaras

Subjects
anti-NMDAR encephalitis, geoepidemiology, seasonality, Biology (General), QH301-705.5
Abstract

Anti-NMDAR encephalitis has been associated with multiple antigenic triggers (i.e., ovarian teratomas, prodromal viral infections) but whether geographic, climatic, and environmental factors might influence disease risk has not been explored yet. We performed a systematic review and a meta-analysis of all published papers reporting the incidence of anti-NMDAR encephalitis in a definite country or region. We performed several multivariate spatial autocorrelation analyses to analyze the spatial variations in the incidence of anti-NMDA encephalitis depending on its geographical localization and temperature. Finally, we performed seasonal analyses in two original datasets from France and Greece and assessed the impact of temperature using an exposure-lag-response model in the French dataset. The reported incidence of anti-NMDAR encephalitis varied considerably among studies and countries, being higher in Oceania and South America (0.2 and 0.16 per 100,000 persons-year, respectively) compared to Europe and North America (0.06 per 100,000 persons-year) (p < 0.01). Different regression models confirmed a strong negative correlation with latitude (Pearson’s R = −0.88, p < 0.00001), with higher incidence in southern hemisphere countries far from the equator. Seasonal analyses showed a peak of cases during warm months. Exposure-lag-response models confirmed a positive correlation between extreme hot temperatures and the incidence of anti-NMDAR encephalitis in France (p = 0.03). Temperature analyses showed a significant association with higher mean temperatures and positive correlation with higher ultraviolet exposure worldwide. This study provides the first evidence that geographic and climatic factors including latitude, mean annual temperature, and ultraviolet exposure, might modify disease risk.

Published
2023
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3. Quantitative brain imaging analysis of neurological syndromes associated with anti-GAD antibodies

Author

Maëlle Dade, Marine Giry, Giulia Berzero, Marion Benazra, Gilles Huberfeld, Delphine Leclercq, Vincent Navarro, Jean-Yves Delattre, Dimitri Psimaras, and Agusti Alentorn

Subjects
Glutamic acid decarboxylase, GAD65 autoimmunity, Volumetry, Cortical thickness, Radiomic data, Neuronal antibodies, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Neurological disorders associated with anti-glutamic acid decarboxylase (GAD) autoimmunity are rare and include a variety of neurological syndromes: stiff-person syndrome, cerebellar ataxia or limbic encephalitis. The diagnosis remains challenging due to the variety of symptoms and normal brain imaging.The morphological MRI of 26 patients (T1-weighted and Fluid-attenuated inversion recovery (FLAIR)-weighted images) was analyzed at the initial stage of diagnosis, matched by age and sex to 26 healthy subjects. We performed a vertex-wise analysis using a generalized linear model, adjusting by age, to compare the brain cortical thickness of both populations. In addition, we used a voxel-based morphometry of cerebellum thickness obtained by CEREbellum Segmentation (CERES), as well as the hippocampus volumetry comparison using HIPpocampus subfield Segmentation (HIPS). Finally, we extracted 62 radiomics features using LifeX to assess the classification performance using a random forest model to identify an anti-GAD related MRI.The results suggest a peculiar profile of atrophy in patients with anti-GAD, with a significant atrophy in the temporal and frontal lobes (adjusted p-value

Published
2021
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4. A human beta cell line with drug inducible excision of immortalizing transgenes

Author

Marion Benazra, Marie-José Lecomte, Claire Colace, Andreas Müller, Cécile Machado, Severine Pechberty, Emilie Bricout-Neveu, Maud Grenier-Godard, Michele Solimena, Raphaël Scharfmann, Paul Czernichow, and Philippe Ravassard

Subjects
Cell engineering, Human pancreatic beta cell line, Conditional immortalization, Tamoxifen inducible CRE, Human beta cell function, Internal medicine, RC31-1245
Abstract

Objectives: Access to immortalized human pancreatic beta cell lines that are phenotypically close to genuine adult beta cells, represent a major tool to better understand human beta cell physiology and develop new therapeutics for Diabetes. Here we derived a new conditionally immortalized human beta cell line, EndoC-βH3 in which immortalizing transgene can be efficiently removed by simple addition of tamoxifen. Methods: We used lentiviral mediated gene transfer to stably integrate a tamoxifen inducible form of CRE (CRE-ERT2) into the recently developed conditionally immortalized EndoC βH2 line. The resulting EndoC-βH3 line was characterized before and after tamoxifen treatment for cell proliferation, insulin content and insulin secretion. Results: We showed that EndoC-βH3 expressing CRE-ERT2 can be massively amplified in culture. We established an optimized tamoxifen treatment to efficiently excise the immortalizing transgenes resulting in proliferation arrest. In addition, insulin expression raised by 12 fold and insulin content increased by 23 fold reaching 2 μg of insulin per million cells. Such massive increase was accompanied by enhanced insulin secretion upon glucose stimulation. We further observed that tamoxifen treated cells maintained a stable function for 5 weeks in culture. Conclusions: EndoC βH3 cell line represents a powerful tool that allows, using a simple and efficient procedure, the massive production of functional non-proliferative human beta cells. Such cells are close to genuine human beta cells and maintain a stable phenotype for 5 weeks in culture.

Published
2015
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5. Copy number variation of mitochondrial genes in Pneumocystis jirovecii according to the fungal load in BAL specimens

Author

clara valero, Maria Jose Buitrago, Maud Gits-Muselli, Marion Benazra, Aude Sturny-Leclere, Samia Hamane, Nicolas Guigue, Stephane Bretagne, and Alexandre Alanio

Subjects
Mitochondria, Pneumocystis jirovecii, Real-Time PCR, PCP, carriage, DNA quantification, Microbiology, QR1-502
Abstract

AbstractPneumocystis jirovecii is an unculturable fungus and the causative agent of Pneumocystis pneumonia, a life-threatening opportunistic infection. Although molecular diagnosis is often based on the mtLSU rRNA mitochondrial gene due to its greater sensitivity, physiology and the dynamics of the mitochondria in this fungus remains largely unknown. We developed and optimized six real-time PCR assays in order to determine the copy number of four mitochondrial genes (mtSSU rRNA, mtLSU rRNA, NAD1 and CYTB) in comparison to nuclear genome (DHPS and HSP70) and tested 84 bronchoalveolar fluids of patients at different stages of the infection. Unexpectedly, we found that copy number of mitochondrial genes varied from gene to gene with mtSSU rRNA gene being more represented (37 copies) than NAD1 (23 copies), mtLSU rRNA (15 copies) and CYTB (6 copies) genes compared to nuclear genome. Hierarchical clustering analysis (HCA) allowed us to define five major clusters, significantly associated with fungal load (p=0.029), in which copy number of mitochondrial genes was significantly different among them. More importantly, copy number of mtLSU rRNA, NAD1 and CYTB but not mtSSU rRNA differed according to P. jirovecii physiological state with a decreased number of copies when the fungal load is low. This suggests the existence of a mixture of various subspecies of mtDNA that can harbor different amplification rates. Overall, we revealed here an unexpected plasticity and dynamics of P. jirovecii mitochondrial DNA that vary according to P. jirovecii’s physiological state.

Published
2016
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6. Tracking the Genetic Susceptibility Background of B-Cell Non-Hodgkin’s Lymphomas from Genome-Wide Association Studies

Author

Agusti Alentorn, Karima Mokhtari, Karim Labreche, Isaias Hernández-Verdin, Khê Hoang-Xuan, Marion Benazra, Gestionnaire, HAL Sorbonne Université 5, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuropathologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Chronic lymphocytic leukemia, Follicular lymphoma, Genome-wide association study, Review, cancer risk, Central Nervous System Neoplasms, lcsh:Chemistry, 0302 clinical medicine, HLA Antigens, Risk Factors, immune system diseases, hemic and lymphatic diseases, GWAS, Lymphoma, Follicular, lcsh:QH301-705.5, Spectroscopy, B-cell non-Hodgkin’s lymphoma, Lymphoma, Non-Hodgkin, Primary central nervous system lymphoma, General Medicine, Lipids, 3. Good health, Computer Science Applications, HLA, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Lymphoma, Large B-Cell, Diffuse, Genetic Background, Risk, Human leukocyte antigen, Biology, Catalysis, Inorganic Chemistry, 03 medical and health sciences, B-cell non-Hodgkin’s lymphom, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Physical and Theoretical Chemistry, Molecular Biology, B cell, Organic Chemistry, Lymphoma, B-Cell, Marginal Zone, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Immunology, Genome-Wide Association Study
Abstract

International audience; B-cell non-Hodgkin's lymphoma (NHL) risk associations had been mainly attributed to family history of the disease, inflammation, and immune components including human leukocyte antigen (HLA) genetic variations. Nevertheless, a broad range of genome-wide association studies (GWAS) have shed light into the identification of several genetic variants presumptively associated with B-cell NHL etiologies, survival or shared genetic risk with other diseases. The present review aims to overview HLA structure and diversity and summarize the evidence of genetic variations, by GWAS, on five NHL subtypes (diffuse large B-cell lymphoma DLBCL, follicular lymphoma FL, chronic lymphocytic leukemia CLL, marginal zone lymphoma MZL, and primary central nervous system lymphoma PCNSL). Evidence indicates that the HLA zygosity status in B-cell NHL might promote immune escape and that genome-wide significance variants can give biological insight but also potential therapeutic markers such as WEE1 in DLBCL. However, additional studies are needed, especially for non-DLBCL, to replicate the associations found to date.

Published
2021
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7. Quantitative brain imaging analysis of neurological syndromes associated with anti-GAD antibodies

Author

Vincent Navarro, Jean-Yves Delattre, Maëlle Dade, Marion Benazra, Agusti Alentorn, Marine Giry, Giulia Berzero, Gilles Huberfeld, Delphine Leclercq, Dimitri Psimaras, Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Gestionnaire, HAL Sorbonne Université 5, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Dade, M., Giry, M., Berzero, G., Benazra, M., Huberfeld, G., Leclercq, D., Navarro, V., Delattre, J. -Y., Psimaras, D., and Alentorn, A.

Subjects
Cerebellum, Pathology, Radiomic data, endocrine system diseases, Hippocampus, Fluid-attenuated inversion recovery, 0302 clinical medicine, Volumetry, Autoimmune epilepsy, Cerebellar ataxia, Neuronal antibodies, 0303 health sciences, Glutamate Decarboxylase, Limbic encephalitis, Brain, Regular Article, 3. Good health, medicine.anatomical_structure, Neurology, Cerebellar atrophy, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, endocrine system, medicine.medical_specialty, Cognitive Neuroscience, Paraneoplastic neurological syndromes, Computer applications to medicine. Medical informatics, R858-859.7, Neuroimaging, Stiff-Person Syndrome, Cortical thickness, 03 medical and health sciences, Atrophy, medicine, Humans, Radiology, Nuclear Medicine and imaging, Stiff-person syndrome, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RC346-429, Autoantibodies, 030304 developmental biology, Glutamic acid decarboxylase, business.industry, nutritional and metabolic diseases, medicine.disease, GAD65 autoimmunity, Neurology. Diseases of the nervous system, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Highlights • The pattern of cortical atrophy is present throughout all anti-GAD phenotypes. • The radiomic features correctly classify anti-GAD patients versus healthy subjects. • The different neurological anti-GAD phenotypes should be considered as a continuum., Neurological disorders associated with anti-glutamic acid decarboxylase (GAD) autoimmunity are rare and include a variety of neurological syndromes: stiff-person syndrome, cerebellar ataxia or limbic encephalitis. The diagnosis remains challenging due to the variety of symptoms and normal brain imaging. The morphological MRI of 26 patients (T1-weighted and Fluid-attenuated inversion recovery (FLAIR)-weighted images) was analyzed at the initial stage of diagnosis, matched by age and sex to 26 healthy subjects. We performed a vertex-wise analysis using a generalized linear model, adjusting by age, to compare the brain cortical thickness of both populations. In addition, we used a voxel-based morphometry of cerebellum thickness obtained by CEREbellum Segmentation (CERES), as well as the hippocampus volumetry comparison using HIPpocampus subfield Segmentation (HIPS). Finally, we extracted 62 radiomics features using LifeX to assess the classification performance using a random forest model to identify an anti-GAD related MRI. The results suggest a peculiar profile of atrophy in patients with anti-GAD, with a significant atrophy in the temporal and frontal lobes (adjusted p-value

Published
2021
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8. Longitudinally Extensive Myelitis Associated With Immune Checkpoint Inhibitors

Author

Julie Perrin, Kevin Bihan, Marc Coustans, Giulia Berzero, Pablo Berlanga, Marion Benazra, Vincent Jachiet, Delphine Leclercq, Cécile Cauquil, Samy Ammari, Perrine Devic, Flavie Bompaire, Jean-Marie Michot, François Ducray, Alberto Picca, Bethsabée Garel, Nora Kramkimel, Dimitri Psimaras, Edouard Januel, Picca, A., Berzero, G., Bihan, K., Jachiet, V., Januel, E., Coustans, M., Cauquil, C., Perrin, J., Berlanga, P., Kramkimel, N., Garel, B., Devic, P., Ducray, F., Benazra, M., Bompaire, F., Leclercq, D., Michot, J. -M., Ammari, S., Psimaras, D., Università di Pavia, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut Gustave Roussy (IGR), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'hématologie [Gustave Roussy], Département d'imagerie médicale [Gustave Roussy], Università degli Studi di Pavia = University of Pavia (UNIPV), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and HAL-SU, Gestionnaire

Subjects
Adult, Male, medicine.medical_specialty, Ataxia, Adolescent, Immune checkpoint inhibitors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Myelitis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Neoplasms, Pharmacovigilance, medicine, Humans, Glucocorticoids, Immune Checkpoint Inhibitors, Severe complication, Aged, Retrospective Studies, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Discontinuation, medicine.anatomical_structure, Neurology, 030220 oncology & carcinogenesis, Concomitant, Sphincter, Female, Neurology (clinical), Immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

ObjectiveTo define the characteristics and the outcome of myelitis associated with immune checkpoint inhibitors (ICIs).MethodsWe performed a retrospective research in the databases of the French Pharmacovigilance Agency and the OncoNeuroTox network for patients who developed myelitis following treatment with ICIs (2011–2020). A systematic review of the literature was performed to identify similar cases.ResultsWe identified 7 patients who developed myelitis after treatment with ICIs (anti-PD1 [n = 6], anti-PD1 + anti-CTLA4 [n = 1]). Neurologic symptoms included paraparesis (100%), sphincter dysfunction (86%), tactile/thermic sensory disturbances (71%), and proprioceptive ataxia (43%). At the peak of symptom severity, all patients were nonambulatory. MRI typically showed longitudinally extensive lesions, with patchy contrast enhancement. CSF invariably showed inflammatory findings. Five patients (71%) had clinical and/or paraclinical evidence of concomitant cerebral, meningeal, caudal roots, and/or peripheral nerve involvement. Despite the prompt discontinuation of ICIs and administration of high-dose glucocorticoids (n = 7), most patients needed second-line immune therapies (n = 5) because of poor recovery or early relapses. At last follow-up, only 3 patients had regained an ambulatory status (43%). Literature review identified 13 previously reported cases, showing similar clinical and paraclinical features. All patients discontinued ICIs and received high-dose glucocorticoids, with the addition of other immune therapies in 8. Clinical improvement was reported for 10 patients.ConclusionMyelitis is a rare but severe complication of ICIs that shows limited response to glucocorticoids. Considering the poor functional outcome associated with longitudinally extensive myelitis, strong and protracted immune therapy combinations are probably needed upfront to improve patient outcome and prevent early relapses.

Published
2021
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9. Neurological Syndromes Associated with Anti-GAD Antibodies

Author

Marine Giry, Dimitri Psimaras, Giulia Berzero, Agusti Alentorn, Marion Benazra, Maëlle Dade, Cristina Izquierdo, Jean-Yves Delattre, Dade, M., Berzero, G., Izquierdo, C., Giry, M., Benazra, M., Delattre, J. -Y., Psimaras, D., Alentorn, A., Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), and Universitat Autònoma de Barcelona (UAB)

Subjects
0301 basic medicine, endocrine system diseases, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Glutamate decarboxylase, Autoimmunity, Review, medicine.disease_cause, lcsh:Chemistry, 0302 clinical medicine, lcsh:QH301-705.5, Autoimmune epilepsy, Spectroscopy, Cerebellar ataxia, Neuronal antibodies, Neurons, education.field_of_study, Glutamate Decarboxylase, Limbic encephalitis, Glutamate receptor, glutamic acid decarboxylase, General Medicine, neuronal antibodies, 3. Good health, Computer Science Applications, medicine.anatomical_structure, medicine.symptom, Stiff person syndrome, endocrine system, autoimmune epilepsy, Cerebellar Ataxia, Paraneoplastic neurological syndromes, Central nervous system, Population, Stiff-Person Syndrome, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, limbic encephalitis, medicine, Humans, Stiff-person syndrome, Physical and Theoretical Chemistry, education, Molecular Biology, Glutamic acid decarboxylase, business.industry, Organic Chemistry, paraneoplastic neurological syndromes, medicine.disease, GAD65 autoimmunity, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Immunology, business, 030217 neurology & neurosurgery
Abstract

Altres ajuts: French National Research Agency (ANR-18-RHUS-0012) Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.

Published
2020
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10. Copy Number Variation of Mitochondrial DNA Genes in Pneumocystis jirovecii According to the Fungal Load in BAL Specimens

Author

Alexandre Alanio, Nicolas Guigue, Marion Benazra, Maud Gits-Muselli, Samia Hamane, María José Buitrago, Stéphane Bretagne, Aude Sturny-Leclère, Clara Valero, Instituto de Salud Carlos III [Madrid] (ISC), Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mycologie moléculaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des Mycoses invasives et antifongiques - Mycologie moléculaire (CNRMA), Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire (CNRMA), Institut Pasteur [Paris], This work was supported by research project PI14CIII/00045 from the Spanish Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III. CV is supported by research fellowships from the Fondo de Investigaciones Sanitarias of the Spanish Ministry of Economy and Competitiveness (FI12/00095)., Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, Microbiology (medical), Mitochondrial DNA, Nuclear gene, [SDV]Life Sciences [q-bio], 030106 microbiology, DNA quantification, lcsh:QR1-502, DHPS, Mitochondrion, Biology, Microbiology, lcsh:Microbiology, PcP, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pneumocystis jirovecii, Copy-number variation, Gene, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Original Research, carriage, Genetics, copy number variation, Ribosomal RNA, biology.organism_classification, Molecular biology, 3. Good health, mitochondria, real-time PCR
Abstract

Pneumocystis jirovecii is an unculturable fungus and the causative agent of Pneumocystis pneumonia, a life-threatening opportunistic infection. Although molecular diagnosis is often based on the detection of mtLSU rRNA mitochondrial gene, the number of copies of mitochondrial genes had not been investigated. We developed and optimized six real-time PCR assays in order to determine the copy number of four mitochondrial genes (mtSSU rRNA, mtLSU rRNA, NAD1, and CYTB) in comparison to nuclear genome (DHPS and HSP70) and tested 84 bronchoalveolar fluids of patients at different stages of the infection. Unexpectedly, we found that copy number of mitochondrial genes varied from gene to gene with mtSSU rRNA gene being more represented (37 copies) than NAD1 (23 copies), mtLSU rRNA (15 copies) and CYTB (6 copies) genes compared to nuclear genome. Hierarchical clustering analysis (HCA) allowed us to define five major clusters, significantly associated with fungal load (p = 0.029), in which copy number of mitochondrial genes was significantly different among them. More importantly, copy number of mtLSU rRNA, NAD1, and CYTB but not mtSSU rRNA differed according to P. jirovecii physiological state with a decreased number of copies when the fungal load is low. This suggests the existence of a mixture of various subspecies of mtDNA that can harbor different amplification rates. Overall, we revealed here an unexpected variability of P. jirovecii mtDNA copy number that fluctuates according to P. jirovecii's physiological state, except for mtSSU that is the most stable and the most present mitochondrial gene. This work was supported by research project PI14CIII/00045 from the Spanish Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III. CV is supported by research fellowships from the Fondo de Investigaciones Sanitarias of the Spanish Ministry of Economy and Competitiveness (FI12/00095). Sí

Published
2016
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11. The Fungal PCR Initiative’s evaluation of in-house and commercial Pneumocystis jirovecii qPCR assays: towards a standard for a diagnostics assay

Author

Gits-Muselli, Maud, White, P. Lewis, Mengoli, Carlo, Chen, Sharon, Crowley, Brendan, Dingemans, Gijs, Fréalle, Emilie, Gorton, Rebecca, Guiver, Malcom, Hagen, Ferry, Halliday, Catriona, Johnson, Gemma, Lagrou, Katrien, Lengerova, Martina, Melchers, Willem Jg, Novak-Frazer, Lily, Rautemaa-Richardson, Riina, Scherer, Emeline, Steinmann, Joerg, Cruciani, Mario, Barnes, Rosemary, Donnelly, J. Peter, Loeffler, Juergen, Bretagne, Stéphane, Alanio, Alexandre, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), International University of Health and Welfare Hospital (IUHW Hospital), Universita degli Studi di Padova, The University of Sydney, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Manchester University NHS Foundation Trust (MFT), University Medical Center [Utrecht], University Hospitals Leuven [Leuven], Mendel University in Brno (MENDELU), Radboud University Medical Center [Nijmegen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University of Duisburg-Essen, Ospedale Fracastoro San Bonifacio [Verona], Cardiff University, Radboud university [Nijmegen], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), We would like to thank Aude Sturny-Leclère, Marion Benazra, and Dirk Schmid for technical assistance and Dr Samia Hamane for her aid in managing the routine diagnosis of PCP. We also thank Pr Anne Bergeron who is in charge of the broncho-alveolar lavage procedure at Saint-Louis hospital, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Padova = University of Padua (Unipd), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Radboud University [Nijmegen], and Julius-Maximilians-Universität Würzburg (JMU)

Subjects
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

Quantitative real-time PCR (qPCR) is increasingly used to detect Pneumocystis jirovecii for the diagnosis of Pneumocystis pneumonia (PCP), but there are differences in the nucleic acids targeted, DNA only versus whole nucleic acid (WNA), and also the target genes for amplification. Through the Fungal qPCR Initiative, a working group of the International Society for Human and Animal Mycology, a multicentre and monocentre evaluation of PCP qPCR assays was performed. For the multicentre study, 16 reference laboratories from eight different countries, performing 20 assays analysed a panel consisting of two negative and three PCP positive samples. Aliquots were prepared by pooling residual material from 20 negative or positive- P. jirovecii bronchoalveolar lavage fluids (BALFs). The positive pool was diluted to obtain three concentrations (pure 1:1; 1:100; and 1:1000 to mimic high, medium, and low fungal loads respectively). The monocentre study compared five in-house and five commercial qPCR assays testing 19 individual BALFs on the same amplification platform. Across both evaluations and for all fungal loads, targeting WNA and the mitochondrial small sub-unit (mtSSU) provided the earliest Cq values, compared to only targeting DNA and the mitochondrial large subunit, the major surface glycoprotein or the beta-tubulin genes. Thus, Reverse Transcriptase-qPCR targeting the mtSSU gene could serve as a basis for standardizing the P. jirovecii load, which is essential if qPCR is to be incorporated into clinical care pathways as the reference method, accepting that additional parameters such as amplification platforms still need evaluation

Published
2019

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